DIGITAL CLOCK DRAWING PERFORMANCE ASSOCIATIONS WITH ALZHEIMER’S DISEASE GENETIC RISK SCORE AND APOE IN OLDER ADULTS

Abstract Alzheimer’s disease (AD) is the leading cause of dementia in older adults, but most people are not diagnosed until clinical signs and symptoms are present. Non-invasive and cost-effective digital biomarkers for AD have the potential to improve early detection. We examined the validity of DCTclockTM (a digitized clock drawing task) as an AD susceptibility biomarker. We used two primary independent variables, Apolipoprotein E (APOE) ɛ4 allele carrier status and polygenic risk score (PRS). We examined APOE and PRS associations with DCTclockTM composite scores as dependent measures. We used existing data from the Framingham Heart Study (FHS), a community-based study with the largest dataset of digital clock drawing data to date. The sample consisted of 2,398 older adults ages 60-94 with DCTclockTM data (mean age of 72.3, 55% female and 92% White). PRS was calculated using 38 variants identified in a recent large genome-wide association study (GWAS) and meta-analysis of late-onset AD (LOAD). Results showed that DCTclockTM performance decreased with advancing age, lower education, and the presence of one or more copies of APOE ε4. Lower DCTclockTM Total Score as well as lower composite scores for Information Processing Speed and Drawing Efficiency were significantly associated with higher PRS levels and more copies of APOE ε4. Associations displayed similar effect sizes in men and women. This is the first study to demonstrate significant differences in clock drawing performance on the basis of APOE status or PRS.

class predicted significantly lower cognitive factors scores at month 48 with one exception -Verbal-Learning & Memory.Ten years later, high-CA women (n=299) scored significantly lower on two factors.MHT predicted neither CA trajectories nor cognitive performance at 48 months or 10 years later.Adiposity levels significantly declined in the high-CA class on MHT but not placebo and was associated with diminished cognitive function.CA influenced short-and long-term cognition.Organ/tissue studies should examine how heterogeneity in adiposity levels interacts with MHT and other factors driving dementia pathogenesis.

COMPARISON OF STEREOLOGY METHODS FOR ASSESSING AGE-RELATED EFFECTS ON IMMUNOSTAINED BRAIN CELLS
Grant Denham 1 , Saeed Alahmari 2 , Aiden Anderson 1 , Krystal Sanchez 1 , Dominick Dag 1 , Lawrence Hall 3 , Dmitry Goldgof 3 , and Peter Mouton 1 , 1. Stereology Resource Center Biosciences,Tampa,Florida,United States,2. Najran University,Najran,Najran,Saudi Arabia,3. University of South Florida,Tampa,Florida,United States The primary benefit of stereology methods is quantification of well-stained biological objects in tissue sections with the ability to adjust sampling intensity to achieve desired levels of precision.The advent of hand-crafted algorithms and artificial intelligence-based deep learning (DL) provides an opportunity for more standardized collection of stereology data with enhanced efficiency and higher reproducibility compared to state-of-the-art manual stereology.We contrasted and compared the performance of four manual, semi-automatic, and fully automatic approaches for generating data for total number of Neu-N immunostained neurons in neocortex (NCTX) in the mouse brain.The gold standard for these studies was manual counts using the state-of-the-art optical fractionator method on 3-D reconstructed serial z-axis image stacks through a known tissue volume (disector stacks).To allow for direct methodological comparisons on the same images, disector stacks were automatically converted into extended depth of field (EDF) images in which all neurons in the disector stack were imaged at each cell's maximal plane of focus.Total number of Neu-N neurons on the same EDF images were counted by a fully automatic hand-crafted method [automatic segmentation algorithm (ASA)] and a semi-automatic method [ASA counts manually corrected for false positives and negatives].All comparison counts were done using unbiased frames and counting rules with total counts of NeuNimmunostained neurons by the optical fractionator method.The results were comparable across methods with wide variations in throughput efficiency and inter-rater agreement.These results are discussed with respect to applications to experimental studies of brain aging, neuroinflammation and neurodegenerative disease.
Abstract citation ID: igad104.2233Alzheimer's disease (AD) is the leading cause of dementia in older adults, but most people are not diagnosed until clinical signs and symptoms are present.Non-invasive and cost-effective digital biomarkers for AD have the potential to improve early detection.We examined the validity of DCTclockTM (a digitized clock drawing task) as an AD susceptibility biomarker.We used two primary independent variables, Apolipoprotein E (APOE) ɛ4 allele carrier status and polygenic risk score (PRS).We examined APOE and PRS associations with DCTclockTM composite scores as dependent measures.We used existing data from the Framingham Heart Study (FHS), a community-based study with the largest dataset of digital clock drawing data to date.The sample consisted of 2,398 older adults ages 60-94 with DCTclockTM data (mean age of 72.3, 55% female and 92% White).PRS was calculated using 38 variants identified in a recent large genome-wide association study (GWAS) and meta-analysis of late-onset AD (LOAD).Results showed that DCTclockTM performance decreased with advancing age, lower education, and the presence of one or more copies of APOE ε4.Lower DCTclockTM Total Score as well as lower composite scores for Information Processing Speed and Drawing Efficiency were significantly associated with higher PRS levels and more copies of APOE ε4.Associations displayed similar effect sizes in men and women.This is the first study to demonstrate significant differences in clock drawing performance on the basis of APOE status or PRS.

DIGITAL CLOCK DRAWING PERFORMANCE ASSOCIATIONS WITH ALZHEIMER'S DISEASE GENETIC RISK SCORE AND APOE IN OLDER ADULTS
Abstract citation ID: igad104.2234

GWAS OF BRAIN ENDOPHENOTYPES: ASSOCIATION OF AUTOPSY-BASED LEWY BODY COUNTS WITH MOVEMENT DISORDER RISK LOCI
Steven Edland 1 , Fernanado Hernandez 1 , Chanond Nasamran 1 , Kathleen Fisch 2 , and Lon White 3 , 1. University of California San Diego, San Diego, California, United States, 2. University of California,San Diego,San Diego,California,United States,3. Pacific Health Research and Education Institute,Honolulu,Hawaii,United States We performed a genome wide association study (GWAS) of neocortical Lewy body density.Case material were 308 autopsies of Japanese-American men (mean age at death 87.5 years; 11% with mild, and 30% with severe cognitive impairment prior to death).Lewy bodies were assessed by manual count of alpha-synuclein stained neocortical sections from the frontal, temporal, parietal, and occipital lobes.Genetic association was tested by linear models controlling for age at death assuming an additive genotypic effect.Top hits include a locus on chromosome 1q32 previously associated with amyotrophic lateral sclerosis (p=5.8e-8),intronic variants on the dopaminergic neuron axonal guidance gene EPHB1 previously associated with Parkinson's disease (PD) (p=8.4e-6), and a locus containing two independent intron 1 variants on CSMD1, a known risk factor for autosomal dominant PD (p=1.5e-6).Complement inhibitor protein CSMD1 is a type 1 transmembrane cell adhesion molecule implicated in axonal guidance and the development, maintenance, and pruning of synapses in the adult brain.Intermediate hits include genes encoding cell adhesion molecules and a second complement inhibitor implicated in the regulation of synapses (TRAPPC9).This converging evidence points to cell adhesion proteins and complement mediated synaptic regulation in the etiology of Lewy body lesions.Cognitive disorders, particularly dementia, are a major cause of disability in the elderly population.Gait disturbances, decreased grip strength and memory complaints are early signs of dementia that can occur well before the disease manifests.To better understand the close interactions between the physical and cognitive domains, the concept of Motoric Cognitive Risk Syndrome (MCRS) has been proposed.We had 25 older adults (10 cognitively unimpaired and 15 with MCRS) generate multiple force pulses at 15% of their maximum voluntary contraction with a fixed duration of 2 seconds for each pulse in which participants must rely on visual spatial abilities to gauge the amount force required in real-time to reach the criterion target.We also assessed neurofilament light chain levels also a blood-based marker of neuronal loss.Our results indicate the MCRS group demonstrated blood oxygenation level dependent (BOLD) hyperactivity in visual cortical/hippocampal regions, parahippocampal regions, and dorsolateral prefrontal cortex.The MCRS group also demonstrated BOLD hypoactivity in primarily involved with movement, such as cerebellar lobules, supplementary motor areas, middle frontal gyrus, and prefrontal cortex areas.beuseful in tracking disease progression.We also found a significant strong positive correlation (0.83) between serum NFL levels and Right BOLD coefficients only for the CI group.This finding suggests that these motor task fMRI measures may be specific in tracking neurodegeneration in MCRS group.Overall, the current preliminary findings provide novel insights into the neurobiological mechanisms underlying early changes in Alzheimer's disease and related dementias.